176 Review Article DOI: 10.1111/j.1610-0387.2008.06639.x Native hyaluronic acid in dermatology results of an expert meeting Luitgard Wiest 1, Martina Kerscher 2 (1) Munich, Germany (2) University of Hamburg, Germany JDDG; 2008 6:176 180 Submitted: 29.8.2007 Accepted: 4.11.2007 Keywords skin aging dermis native hyaluronic acid Summary The glycosaminoglycan hyaluronic acid (HA) is a major component of the extracellular matrix of the skin and plays an important role in the metabolism of the dermis. HA is responsible for hydration, nutrient exchange and protects against free radical damage; via signaling pathways it is also involved in biologic processes like cell differentiation and motility. Native HA has been employed for several years to help the skin to regain elasticity, turgor and moisture. In a clinical study an increase in elasticity and turgor following repeated injections with HA could be demonstrated, but this treatment approach is discussed controversially. An expert conference took place to find a consensus regarding use, aims of treatment, indications and limitations of this therapy. The decisions of the expert meeting are presented in this report. Introduction For several years, injections with native, non-cross-linked hyaluronic acid have been performed in dermatology in order to provide the skin with more elasticity, turgor and moisture. To evaluate the role of treatment with native hyaluronic acid and to formulate treatment recommendations, an expert conference was held on May 16 and 17, 2007 in the course of the 16 th Congress of the European Academy of Dermatology and Venereology (EADV) 2007 in Vienna, Austria with the support of Merz Pharmaceuticals, Frankfurt/Main, Germany. Participants of the expert conference were Rolf Berg, Rösrath, Lisette Gerke, Düsseldorf, Martina Herholz, Frankfurt, Matthias Imhof, Bad Soden, Bernd Kardorff, Mönchengladbach, Ulrich Kühne, Bad Soden, Harald Kuschnir, Grünwald, Sarah Masri, Berlin, Roland Mett, Schwerin, Yasemin Özen, Nuremberg, Johannes Reinmüller, Wiesbaden, Bettina Rümmelein, Kronberg, Marianne Wolters, Frankfurt. The chairpeople were Martina Kerscher, Hamburg and Luitgard Wiest, Munich (all Germany). Scientific background The role of hyaluronic acid in skin metabolism Native hyaluronic acid is a linear polysaccharide composed of disaccharide units containing N-acetylglucosamine and glucuronic acid [1]. It is one of the main constituents of the extracellular matrix (ECM) and is therefore indispensable for the cellular framework [2]. Hyaluronic acid possesses a large waterbinding capacity. It thus is responsible for hydration of the skin and increases its moisture content [3]. Further, it plays a major role in exchange between cells and blood and for cell migration. Recent research studies suggest that hyaluronic acid, via the CD44 receptor, is capable of increasing cell differentiation [3]; via the receptor for hyaluronic acid-mediated motility (RHAMM), but also via the CD44 receptor, it increases cell motility [4]. Via RHAMM, cell migration during wound healing is promoted. In an experimental study addition of hyaluronic acid to dermal fibroblast cultures lead to transient DNA synthesis with a consecutive Dt. Dermatologische Gesellschaft u. a. Journal compilation Blackwell Verlag, Berlin JDDG 1610-0379/2008/0603-0176
Native hyaluronic acid in dermatology Review Article 177 increase in the cell count of over 20 % [5]. This is of special importance due to the fact that fibroblasts in aged skin divide only slowly. In fibroblasts in vitro the production of endogenous hyaluronic acid, collagen and elastin is stimulated [6]. A further major function of hyaluronic acid is to protect the cell from damage by free radicals that play a large role in skin aging [1, 7, 8]. The most important roles of native hyaluronic acid in skin metabolism can be summarized as following: increases water-binding capacity, influences cell motility, protects cells from free radicals, promotes cell-to-cell communication, has anti-inflammatory properties and promotes wound healing [9]. Even cross-linked, i.e. chemically altered hyaluronic acid, as employed in dermal fillers, is not completely biologically inert. Based on a recent study, it stimulates collagen synthesis by activating fibroblasts [10]. Loss of epidermal hyaluronic acid during aging With age the epidermal concentration of hyaluronic acid declines progressively [3]. In women aged 19 to 47 years it still is 0.03 %; in over 60-year-olds, only 0.015 %; and in 70-year-olds even only 0.007 % [11]. Simultaneously during aging a reduction and structural changes of collagen fibers occur. All factors lead to dehydration, atrophy and loss of elasticity characteristic of aged skin [3]. Clinical studies on the effects of injections with native hyaluronic acid With regards to treatment of elastotic skin with native hyaluronic acid, one study using the product Hyal-System shows positive effects on skin elasticity and turgor [12]. Twenty patients with distinct to substantial signs of aging of the facial skin (mean age: 52 years) received two treatments with native hyaluronic acid at an interval of 14 days in this study. Turgor and elasticity were significantly improved by this. Of physicians and patients 95 % each judged the treatment results as very good or good [12]. A still unpublished current single center study using the same product showed that hyaluronic acid injections in comparison to injections with physiologic saline solution cause the skin to gain firmness. The increase in skin firmness also improves the surface features of the skin as well as the water content of the stratum corneum. Voting results of the consensus conference As to the procedure, the methodic recommendations of the Association of the Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) were followed [13]. An interdisciplinary team of experts consisting of dermatologists and plastic surgeons was recruited, developed consensus recommendations on the use of hyaluronic acid. When at least 60 %, i.e. 9 experts, voted yes, it was rated as a majority opinion, when at least 80 %, i. e. 12 experts voted yes, it was rated as consensus. Table 1 provides a review of expert voting. Target parameters for skin rejuvenation with hyaluronic acid All experts were of the opinion that skin elasticity is the best parameter to measure the effects of treatment with native hyaluronic acid. Of the 15 experts, 14 considered changes in the surface structure as another important parameter of efficacy. Consensus was established, that with an extensive surface treatment with native hyaluronic acid elasticity, surface structure, moisture and turgor of the skin could be improved, for which many clinical examples exist (Figures 1 and 2). Indication spectrum of native hyaluronic acid Indications in dermatology Treatment with native hyaluronic acid in the face can improve dry aged skin as well as extrinsically damaged skin, e. g. due to smoking or UV radiation. Treatment is especially sensible even in early stages of solar elastosis. All experts were of the opinion that selection criteria for treatment with native hyaluronic acid should be fine, superficial wrinkles and/or beginning loss of elasticity. Even in cases of severe loss of elasticity, improvement can be attained. Most frequently cheeks, neck and décolleté are treated with native hyaluronic acid. Further, the treatment is suited for peri- and infraorbital, and perioral skin regions as well as for the backs of the hands and décolleté. In the periorbital area the combination with botulinum toxin A (BTX-A) can optimize total aesthetic features. In the lower half of the face, too, e. g. at the oral commissures in case of a strong mimic component, combination with BTX-A may be initiated. Consensus existed that in the case of deep wrinkles treatment with native hyaluronic acid is only useful when done in combination with absorbable hyaluronic fillers. Indications in connection with aestheticsurgical procedures When tautening procedures are performed on the face and/or neck, some patients remain disturbed by seemingly persistent fine wrinkles. In this case treatment with native hyaluronic acid can improve skin character and thus optimize the general aesthetic outcome. Treatment can be performed after the resolution of swelling, i.e. about 4 8 weeks after surgery. Of the 15 experts 14 judged treatment with native hyaluronic acid as a adjuvant procedure after surgical tautening procedures. Treatment techniques for using native hyaluronic acid Native hyaluronic acid can be applied either manually or with the help of an injection pistol. Advantages of the injection pistol are that the application produces less pain, treatment can be performed more quickly and wheals recede more rapidly. Of course, the hyaluronic acid must be diluted with the effect that its concentration at the injection site is lower than with manual injection. Clinical studies which prove efficacy have been done only with the manual injection technique. For this reason, all experts were of the opinion that manual injection of native hyaluronic acid should be preferred over application with injection pistols. The vote of the experts is unanimous with regard to the treatment technique: Accordingly, the serial point technique for injecting native hyaluronic acid is the gold standard (Figure 3). Serially making wheals in the skin is easy to do, has few side effects and is efficient. Alternative techniques (criss-cross, tunnel, fan technique) are less recommended because they are more difficult to perform and have increased side effects.
178 Review Article Native hyaluronic acid in dermatology Table 1: Role of native hyaluronic acid in aesthetic medicine voting results of the consensus conference. Blue = consensus. Recommendations/statements Voting result Target parameters of treatment Skin elasticity (skin fatigue/firmness) is the best parameter for efficacy of this treatment. Change in skin surface structure is a further parameter for efficacy of this treatment. 14/15 Native hyaluronic acid is suitable for extensive superficial treatment of the skin with the goal of improving elasticity, surface structure, moisture and turgor. 14/15 Treatment regions Periorbital region: Hyal-System leads to an improvement of elasticity, the combination with BTX-A optimizes the aesthetic features. Oral commissures (upper lip area): When mimic component is present, the combination with BTX-A is recommended. Selection criteria for treatment 14/15 Selection criteria are fine superficial wrinkles, even in cases of severe loss elasticity, improvement can be achieved. This treatment is a sensible adjuvant measure following tautening surgical procedures in the face and neck area. 14/15 Treatment techniques The serial point technique is the gold standard, as it is easy to perform, has few side effects and is efficient. Alternative techniques are less recommendable. Accompanying phenomena are mild and completely reversible. Obligate wheal formation is a sign of correct superficial intradermal injection. The implantation by manual serial puncture technique is preferable over the use of an injection pistol. Combination treatments For deeper wrinkles a combination with absorbable hyaluronic acid fillers should be performed. The combination treatment with suitable hyaluronic acid fillers in one session is possible and often sensible. The combination with BTX-A especially in the perioral and periorbital region should be performed in two sessions, as the diffusion behavior of BTX-A can be altered. 8/15 Tolerability of treatment with native hyaluronic acid is very good. All experts were of the opinion that accompanying phenomena were only mild and transient. The formation of a wheal is regarded as a sign of the correct intradermal injection. Figure 1: 68-year-old woman treated at 3 month intervals for a longer period of time with Hyal-System : status before the last treatment. Source: M. Imhof, U. Kühne, Bad Soden, Germany. Procedure in combination treatment If a combination treatment with native hyaluronic acid together with suitable absorbable dermal fillers is planned, it is possible and often done in one session. Altogether, consensus was not possible for one decision, namely if treatment with BTX-A and native hyaluronic acid is possible in one session. Eight experts were of the opinion that the combination with BTX-A especially in the perioral and periorbital region should be per-
Native hyaluronic acid in dermatology Review Article 179 Source Expert conference The role of native hyaluronic acid in aesthetic medicine, held on May 16, 2007 in the course of the 16 th Congress of the European Academy of Dermatology and Venereology (EADV) 2007 in Vienna, Austria Conflict of interest None. Figure 2: 68-year-old woman after repeated treatment with Hyal-System : status 4 weeks after last treatment. The skin has gained elasticity and turgor, small wrinkles have disappeared. Source: M. Imhof, U. Kühne, Bad Soden, Germany. Figure 3: Serial point technique with wheal formation. Source: L. Wiest, Munich, Germany. formed in two sessions, as the diffusion characteristics of BTX-A might be affected, while seven experts had no hesitation to perform the treatment in a single session. Conclusions Treatment with native hyaluronic acid is a non-invasive method for extensive superficial treatment of aging facial skin. So far, the clinical studies were performed with the product Hyal-System. Skin elasticity is the best parameter to judge the efficacy of this method. Crucial for treatment success is the selection of adequate indications and adequate treatment techniques. Consensus was found among the experts even on these points. Often the use of native hyaluronic acid in combination with other methods is sensible in aesthetic dermatology. In the opinion of all experts, treatment with native hyaluronic acid is a useful method for the extensive superficial treatment of skin with the goal of improving elasticity, surface structure, moisture and turgor. Correspondence to Dr. L. Wiest Residenzstraße 7 D-80333 Munich, Germany Tel.: +49-89-23 24-11 31 Fax: +49-89-23 24-11 32 E-mail: lwiest@ivprojekt.com References 1 Scott JE. Hyaluronan, multum in parvo. Eur J Rheumatol Inflamm 1995; 15(1): 3 8. 2 Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution, functions and turnover. J Intern Med 1997; 242: 27 33. 3 Neudecker BA, Csoka AB, Mio K, Maibach HI, Stern R. Hyaluronan: the natural skin moisturizer. In: Elsner P, Maibach HI: Cosmeceuticals Drugs vs. Cosmetics. 1. Auflage. New York: Marcel Dekker Verlag, 2000. 4 Nehls V, Hayen W. Are hyaluronan receptors involved in three-dimensional cell migration? Histol Histopathol 2000; 15(2): 629 636. 5 Yoneda M, Yamagata M, Suzuki S, Kimata K. Hyaluronic acid modulates proliferation of mouse dermal fibroblasts in culture. J Cell Sci 1988; 90: 265 273. 6 Lapiere CM. The ageing dermis: the main cause for the appearance of old skin. Br J Dermatol 1990; 122(Suppl 35): 5 11. 7 Scott JE, Cummings C, Brass A, Chen Y. Secondary and tertiary structures of hyaluronan in aqueous solution, investigated by rotary shadowing-electron microscopy and computer simulation. Hyaluronan is a very efficient networkforming polymer. Biochem J. 1991; 274: 699 705. 8 Presti D, Scott JE. Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass.
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